Abstract
BackgroundTranscutaneous immunization (TCI) approaches utilize skin associated lymphatic tissues to elicit specific immune responses. In this context, the imidazoquinoline derivative imiquimod formulated in Aldara applied onto intact skin together with a cytotoxic T lymphocyte (CTL) epitope induces potent CTL responses. However, the feasibility and efficacy of the commercial imiquimod formulation Aldara is limited by its physicochemical properties as well as its immunogenicity.Methodology/Principal FindingsTo overcome these obstacles, we developed an imiquimod-containing emulsion gel (IMI-Gel) and characterized it in comparison to Aldara for rheological properties and in vitro mouse skin permeation in a Franz diffusion cell system. Imiquimod was readily released from Aldara, while IMI-Gel showed markedly decreased drug release. Nevertheless, comparing vaccination potency of Aldara or IMI-Gel-based TCI in C57BL/6 mice against the model cytotoxic T-lymphocyte epitope SIINFEKL, we found that IMI-Gel was equally effective in terms of the frequency of peptide-specific T-cells and in vivo cytolytic activity. Importantly, transcutaneous delivery of IMI-Gel for vaccination was clearly superior to the subcutaneous or oral route of administration. Finally, IMI-Gel based TCI was at least equally effective compared to Aldara-based TCI in rejection of established SIINFEKL-expressing E.G7 tumors in a therapeutic setup indicated by enhanced tumor rejection and survival.Conclusion/SignificanceIn summary, we developed a novel imiquimod formulation with feasible pharmaceutical properties and immunological efficacy that fosters the rational design of a next generation transcutaneous vaccination platform suitable for the treatment of cancer or persistent virus infections.
Highlights
Transcutaneous immunization (TCI) approaches are increasingly gaining interest by vaccine developers since they incorporate all desirable properties of an ideal cancer vaccine, in terms of defined antigen specificities, targeting of specific APC populations and well-defined adjuvants [1,2]
We have previously shown that the concurrent administration of a cytotoxic T lymphocyte (CTL) epitope together with the TLR7 agonist imiquimod onto intact skin elicits potent primary CTL responses [8]
While classical prophylactic vaccination approaches are suitable for inducing protective antibody responses against virus infections, they may not be ideal for the induction of therapeutic T-cell responses
Summary
Transcutaneous immunization (TCI) approaches are increasingly gaining interest by vaccine developers since they incorporate all desirable properties of an ideal cancer vaccine, in terms of defined antigen specificities, targeting of specific APC populations and well-defined adjuvants [1,2]. Needle-borne accidents in both medical personnel and patients will be circumvented. From an immunological point of view the skin is an attractive target for shaping immune responses: the delivery of antigens is controlled and targeted to skin resident APC [5] in direct conjunction with an adjuvant eliciting potent adaptive immune responses as pioneered by Glenn and coworkers [6]. Transcutaneous immunization (TCI) approaches utilize skin associated lymphatic tissues to elicit specific immune responses. In this context, the imidazoquinoline derivative imiquimod formulated in Aldara applied onto intact skin together with a cytotoxic T lymphocyte (CTL) epitope induces potent CTL responses. The feasibility and efficacy of the commercial imiquimod formulation Aldara is limited by its physicochemical properties as well as its immunogenicity
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